JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F19%3A00070539" target="_blank" >RIV/65269705:_____/19:00070539 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14110/19:00108952

Result on the web

<a href="https://www.nature.com/articles/s41375-018-0295-6" target="_blank" >https://www.nature.com/articles/s41375-018-0295-6</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41375-018-0295-6" target="_blank" >10.1038/s41375-018-0295-6</a>

Result language

angličtina

Original language name

JAK2V617F but not CALR mutations confer increased molecular responses to interferon-alpha via JAK1/STAT1 activation

Original language description

Pegylated interferon-alpha (peg-IFNa) treatment induces molecular responses (MR) in patients with myeloproliferative neoplasms (MPNs), including partial MR (PMR) in 30-40% of patients. Here, we compared the efficacy of IFNa treatment in JAK2V617F-vs. calreticulin (CALR)-mutated cells and investigated the mechanisms of differential response. Retrospective analysis of MPN patients treated with peg-IFNa demonstrated that patients harboring the JAK2V617F mutation were more likely to achieve PMR than those with mutated CALR (p = 0.004), while there was no significant difference in hematological response. In vitro experiments confirmed an upregulation of IFN-stimulated genes in JAK2V617F-positive 32D cells as well as patient samples (peripheral blood mononuclear cells and CD34+ hematopoietic stem cells) compared to their CALR-mutated counterparts, and higher IFNa doses were needed to achieve the same IFNa response in CALR- as in JAK2V617F-mutant 32D cells. Additionally, Janus-activated kinase-1 (JAK1) and signal transducers and activators of transcription 1 (STAT1) showed constitutive phosphorylation in JAK2V617F-mutated but not CALR-mutated cells, indicating priming towards an IFNa response. Moreover, IFN-induced growth arrest was counteracted by selective JAK1 inhibition but enhanced by JAK2 inhibition. In conclusion, our data suggest that, clinically, higher doses of IFNa are needed in CALR-mutated vs. JAK2V617F-positive patients and we suggest a model of JAK2V617F-JAK1/ STAT1 crosstalk leading to a priming of JAK2V617F-positive cells to IFNa resulting in differential sensitivity

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30204 - Oncology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Leukemia

ISSN

0887-6924

e-ISSN

—

Volume of the periodical

33

Issue of the periodical within the volume

4

Country of publishing house

GB - UNITED KINGDOM

Number of pages

16

Pages from-to

995-1010

UT code for WoS article

000463162400014

EID of the result in the Scopus database

2-s2.0-85057149022